In search of new treatments and a possible biomarker, preclinical research will focus on epigenetic factors in Alzheimer’s disease

“We hypothesize that Alzheimer’s is produced by a combination of genetic risk factors and environmental factors, such as aging, that induce the dysregulation of specific epigenetic processes that, in turn, lead to impaired cognition.”

Zhen Yan, PhD, Professor, Dept. of Physiology and Biophysics

Jacobs School of Medicine and Biomedical Sciences

BUFFALO, N.Y. — While most research on Alzheimer’s
disease (AD) has focused on early diagnosis and treatment,
University at Buffalo scientists are studying genetic and
epigenetic factors with the ultimate goal of restoring function to
patients in the later stages of the disease.

The UB team’s research will include studies in mouse
models carrying gene mutations for familial AD (where more than one
member of a family has the disease) and in human stem cell-derived
neurons from AD patients.

Zhen Yan, PhD, principal investigator, and Jian Feng, PhD,
co-investigator, both professors in the Department of Physiology
and Biophysics in the Jacobs School of Medicine and Biomedical
Sciences at UB, have received a five-year, $2 million grant from
the National Institutes of Health to conduct preclinical research
to tease out genetic and epigenetic factors that cause
Alzheimer’s disease. Epigenetic factors can change gene
expression by altering the way that gene promoters, which initiate
the copying of genetic information known as transcription, access
the cellular machinery that conducts transcription. Such changes
may profoundly impact human health.

“We hypothesize that Alzheimer’s is produced by a
combination of genetic risk factors and environmental factors, such
as aging,” said Yan, “that induce the dysregulation of
specific epigenetic processes that, in turn, lead to impaired
cognition.”

The UB research will explore how epigenetic changes that
accompany Alzheimer’s disease also might help identify a much
sought-after biomarker for the disease, which could, in turn, allow
for novel treatment.

Numerous clinical trials in recent years have focused on
reducing amyloid beta plaque in the brain. So far, such efforts
haven’t yet translated into improving cognitive function, Yan
said.

“Our research, by contrast, will target synaptic function,
which is at the root of cognitive function,” she explained.
“The idea is that this approach will have a more fundamental
effect.”

She and her colleagues will investigate aberrant histone
methylation, an epigenetic process that affects the expression of
genes encoding key proteins that allow for signals to be
transmitted between neurons.

When this process is dysregulated in Alzheimer’s disease,
neuronal signaling doesn’t function properly, leading to
cognitive impairment.

As those with loved ones with Alzheimer’s know, even
though the patient can easily remember something that happened 20
years ago, the later stages are characterized by a growing
inability to recall recently learned information. That kind of
short-term memory, Yan explained, is dependent on excitatory
transmission in the frontal cortex, mediated by glutamate
receptors.

“At the later stages of the disease, we know that there is
a loss of glutamate receptors that are crucial for learning and
memory,” she said. “When these receptors lose the
ability to communicate, there is a loss of cognition. Our research
will try to restore gene expression in these glutamate receptors
using epigenetic tools, with the ultimate goal of restoring
cognitive function.”